Abstract

Background

The phase III RECOURSE trial demonstrated that TAS-102, an oral fixed-combination drug consisting of trifluridine and tipiracil hydrochloride, significantly improved overall survival compared with placebo for refractory metastatic colorectal cancer. Preclinical studies showed TAS-102 additively enhanced the anticancer effect of irinotecan (CPT-11), and the phase I study of TAS-102 administrated on days 1-5 and 8-12 of a 28-day cycle with a fixed dosage of CPT-11 (150 mg/m2) every 2 weeks in Japanese patients demonstrated that the maximum tolerated dose (MTD) of TAS-102 was 30 mg/m2/BID. This combination therapy showed the expected antitumor activity, although the relative dose intensity of CPT-11 was low due to hematological toxicities. Now, we conduct a phase Ib study of biweekly TAS-102 (day 1-5 of a 14-days cycle) with CPT-11 and bevacizumab every 2 weeks.

Trial design

The study is conducted in 2 parts: a dose-escalation part (part 1) to determine the MTD and an expansion part (part 2) to further evaluate the safety and preliminary efficacy. Eligibility criteria include histologically proven colorectal adenocarcinoma, failure to first-line chemotherapy with fluoropyrimidine and oxaliplatin, age of 20-75 years, ECOG PS of 0–1, and adequate organ function. The primary endpoint of part 1 is incidence of the dose-limiting toxicity (DLT) of TAS-102, CPT-11 and bevacizumab (5 mg/kg), and that of part 2 is incidence of febrile neutropenia (FN). DLTs include prolonged (> 7 days) grade 4 neutropenia and FN. Five dose levels of TAS-102 and CPT-11 are planned as follows; Level 1: TAS-102 25 mg/m2/BID CPT-11 180 mg/m2, Level 2a: TAS-102 30 mg/m2/BID CPT-11 180 mg/m2, Level 3a: TAS-102 35 mg/m2/BID CPT-11 180 mg/m2, Level 2b: TAS-102 30 mg/m2/BID CPT-11 150 mg/m2, Level 3b: TAS-102 35 mg/m2/BID CPT-11 150 mg/m2. In part 1, patients undergo a 3 + 3 design schema to evaluate the DLT. The recommended dose is defined as the highest dose level where no more than 2 of 6 patients experience a DLT during 2 cycles.

Clinical trial indentification

This study is registered to the University Hospital Medical Information Network (UMIN000019828), and activated in August 2016.

Legal entity responsible for the study

Shizuoka Cancer Center and Aichi Cancer Center Hospital

Funding

Taiho Pharma

Disclosure

H. Taniguchi, K. Muro: honoraria by Taiho Pharma. K. Yamazaki: honoraria and research funding by Taiho Pharma. All other authors have declared no conflicts of interest.